The study of anti-HIV nucleosides bearing a conventional 2-deoxyribose backbone continued, maintaining rather than eliminating the 3-OH group, but adding a 4-alkyl group (methyl and ethyl) to interfere with the chain elongation step. The recent synthesis of the corresponding 4-methyl-2-deoxyadenosine series provided a compound that is both successfully phosphorylated by cellular kinases and extremely potent against HIV in infected cells. This represents the first successful design of a compound in this class capable of being activated by cellular kinases and able to function as an effective delay (kinetic delay) chain terminator of viral DNA synthesis. A US patent was filed. Studies on another compound, D-carbathymidine, which is also phosphorylated by cellular enzymes and active against all HIV-resistant strains, represents an important step forward in our drug design efforts to overcome HIV resistance. The investigations on the mechanism of this compound will appear soon (J. Med. Chem. in press). The syntheses of conformationally locked and flat bicyclo[3.1.0]hex-3-ene nucleosides in both north and south hemisphere of the pseudorotational cycle containing thymine, cytosine, guanine, and adenine as nucleobases were completed. The most active compounds bearing adenine and thymine rings reside in the North hemisphere. These results were published recently in ChemMedChem and the graphical abstract of the work was selected for the cover page of the journal (ChemMedChem 2009, in press). The goal of this project is to use fundamental drug design principles derived from our knowledge about the mechanism of HIV reverse transcription to synthesize new molecules that might function as delayed chain terminators, and work as efficient substrates for the activating cellular kinases.